Dataset and standard operating procedure for newborn screening of six lysosomal storage diseases: By tandem mass spectrometry

In this data article we provide a detailed standard operating procedure for performing a tandem mass spectrometry, multiplex assay of 6 lysosomal enzymes for newborn screening of the lysosomal storage diseases Mucopolysaccharidosis-I, Pompe, Fabry, Niemann-Pick-A/B, Gaucher, and Krabbe, (Elliott, et al., 2016) [1]. We also provide the mass spectrometry peak areas for the product and internal standard ions typically observed with a dried blood spot punch from a random newborn, and we provide the daily variation of the daily mean activities for all 6 enzymes

Synthesis and Anti-Chagas Activity Profile of a Redox-Active Lead 3-Benzylmenadione Revealed by High-Content Imaging

Chagas’ disease or American trypanosomiasis is a neglected tropical disease, which is a top priority target of the World Health Organization. The disease, endemic mainly in Latin America, is caused by the protozoan Trypanosoma cruzi and has spread around the globe due to human migration. There are multiple transmission routes, including vectorial, congenital, oral and iatrogenic. Less than 1% of patients have access to treatment, relying on two old redox-active drugs that show poor pharmacokinetics and severe adverse effects. Hence, the priorities for the next steps of R&D include i) the discovery of novel drugs/chemical classes; ii) filling the pipeline with drug candidates that have new mechanisms of action, iii) the pressing need for more research and access to new chemical entities. In the present work, we first identified a hit (4a) with a potent anti-T. cruzi activity from a library of 3-benzylmenadiones. We then designed a synthetic strategy to build a library of 49 3-(4-monoamino) benzylmenadione derivatives, via reductive amination to obtain diazacyclic benz(o)ylmenadiones. Among them, we identified by high content imaging an anti-amastigote “early lead” 11b (henceforth called cruzidione) revealing optimized pharmacokinetic properties and enhanced specificity. Studies in a yeast model revealed that a cruzidione metabolite, the 3-benzoylmenadione (cruzidione oxide), enters redox-cycling with the NADH-dehydrogenase, generating reactive oxygen species, as hypothesized for the early hit (4a)

Synthesis and anti-Chagas activity profile of a novel redox-active lead 3-benzylmenadione revealed by high-content imaging

Chagas’ disease or American trypanosomiasis is a neglected tropical disease, which is a top priority target of the World Health Organization. The disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America and has spread around the globe due to human migration. There are multiple transmission routes, from vectorial, congenital, oral to iatrogenic. Less than 1% of patients have access to treatment, limited to two old redox-active drugs, but these have poor pharmacokinetics and severe adverse effects. Hence, the priorities for the next steps of R&D include i) the discovery of new drugs/chemical classes for clinical trials; ii) filling the pipeline with drug candidates that have new mechanisms of action, iii) the need for more research and access to new chemical entities. In the present work, we first identified a hit (4a), from a library of 3-benzylmenadiones, that had potent anti-T.cruzi activity. We then designed a synthetic strategy to build a library of 49 3-(4-mono-amino)benzylmenadione derivatives, via reductive amination to obtain diazacyclic benz(o)ylmenadiones. Among them, we identified an anti-amastigote “early lead” 11b (henceforth called cruzidione) by high content imaging with optimized pharmacokinetic properties and better specificity. Studies in a yeast model revealed that a cruzidione metabolite, the 3-benzoylmenadione (cruzidione oxide), enters redox-cycling with the NADH-dehydrogenase, generating reactive oxygen species, as hypothesized for the early hit (4a)

Synthesis and anti-Chagas activity profile of a redox-active lead 3benzylmenadione revealed by high-content imaging

International audienceChagas’ disease or American trypanosomiasis is a neglected tropical disease, which is a top priority target of the World Health Organization. The disease, endemic mainly in Latin America, is caused by the protozoan Trypanosoma cruzi and has spread around the globe due to human migration. There are multiple transmission routes, including vectorial, congenital, oral and iatrogenic. Less than 1% of patients have access to treatment, relying on two old redox-active drugs that show poor pharmacokinetics and severe adverse effects. Hence, the priorities for the next steps of R&D include i) the discovery of novel drugs/chemical classes; ii) filling the pipeline with drug candidates that have new mechanisms of action, iii) the pressing need for more research and access to new chemical entities. In the present work, we first identified a hit (4a) with a potent anti-T. cruzi activity from a library of 3-benzylmenadiones. We then designed a synthetic strategy to build a library of 49 3-(4-mono-amino)benzylmenadione derivatives, via reductive amination to obtain diazacyclic benz(o)ylmenadiones. Among them, we identified by high content imaging an anti-amastigote “early lead” 11b (henceforth called cruzidione) revealing optimized pharmacokinetic properties and enhanced specificity. Studies in a yeast model revealed that a cruzidione metabolite, the 3-benzoylmenadione (cruzidione oxide), enters redox-cycling with the NADH-dehydrogenase, generating reactive oxygen species, as hypothesized for the early hit (4a)

Synthesis and Anti-Chagas Activity Profile of a Redox-Active Lead 3‑Benzylmenadione Revealed by High-Content Imaging

Chagas disease, or American trypano­somiasis, is a neglected tropical disease which is a top priority target of the World Health Organization. The disease, endemic mainly in Latin America, is caused by the protozoan Trypanosoma cruzi and has spread around the globe due to human migration. There are multiple transmission routes, including vectorial, congenital, oral, and iatrogenic. Less than 1% of patients have access to treatment, relying on two old redox-active drugs that show poor pharmaco­kinetics and severe adverse effects. Hence, the priorities for the next steps of R&D include (i) the discovery of novel drugs/chemical classes, (ii) filling the pipeline with drug candidates that have new mechanisms of action, and (iii) the pressing need for more research and access to new chemical entities. In the present work, we first identified a hit (4a) with a potent anti-T. cruzi activity from a library of 3-benzyl­menadiones. We then designed a synthetic strategy to build a library of 49 3-(4-monoamino)­benzyl­menadione derivatives via reductive amination to obtain diazacyclic benz(o)yl­menadiones. Among them, we identified by high content imaging an anti-amastigote “early lead” 11b (henceforth called cruzidione) revealing optimized pharmaco­kinetic properties and enhanced specificity. Studies in a yeast model revealed that a cruzidione metabolite, the 3-benzoyl­menadione (cruzidione oxide), enters redox cycling with the NADH-dehydrogenase, generating reactive oxygen species, as hypothesized for the early hit (4a)